Dementia is the progressive decline in cognitive function due to damage or a disease in the brain beyond what might be expected from normal aging. The most well-known type of dementia is Alzheimer's disease.
Alzheimer's disease (AD) is an increasingly prevalent form of neurodegeneration that accounts for approximately 50%-60% of the overall cases of dementia among people over 65 years of age. It currently affects an estimated 24 million people worldwide owing to the relative increase of elderly people in the population. Its prevalence is likely to increase over the next 2 to 3 decades. AD is a progressive disorder with a mean duration of around 8.5 years between onset of clinical symptoms and death. Death of pyramidal neurons and loss of neuronal synapses in brain regions associated with higher mental functions results in the typical symptoms, characterized by gross and progressive impairment of cognitive function (see Francis, P. T., et al., J. Neurol. Neurosurg. Psychiatry (1999) 66: 137-147). Clinical signs of Alzheimer's disease are characterized by progressive cognitive deterioration, together with declining activities of daily living and by neuropsychiatric symptoms or behavioral changes.
Neuropathologically, the major hallmarks of AD are the presence of two characteristic lesions: the amyloid senile plaque and neurofibrillary tangle (NFT). While the plaque is deposited extraneuronally, the tangle is observed intraneuronally in the post-mortem brain. One of the major components of the amyloid plaque core is the pathologically deposited small amyloid-beta-peptide (Aβ), which is cleaved by secretases from amyloid precursor protein (APP) (see Selkoe, D. J., Physiol. Rev. (2001) 81: 741-766; Hardy, J. and Selkoe, D. J., Science (2002) 297: 353-356). Aβ, a self-aggregating peptide of 39-43 residues (MW˜4 kDa), is synthesized as part of the larger APP (110-120 kDa). APP is a type I integral membrane glycoprotein with a large N-terminal extracellular domain, a single transmembrane domain and a short cytoplasmic tail. The AP region spans portions of the extracellular and transmembrane domains of APP. The most common hypothesis for the participation of APP in neuronal cell death in AD is the amyloid hypothesis. This hypothesis postulates that plaque amyloid depositions or partially aggregated soluble Aβ trigger a neurotoxic cascade, thereby causing neurodegeneration similar to AD pathology (see Selkoe, D. J., Physiol. Rev. (2001) 81: 741-766; Hardy, J. and Selkoe, D. J., Science (2002) 297: 353-356).
Currently available medications can help reduce the symptoms of the disease, but they cannot change the course of the underlying pathology. There is currently no cure for Alzheimer's disease. There is still a need to provide a method for the treatment and/or prevention of age-related dementia, especially Alzheimer's disease.
Polygonum multiflorum is also commonly known as shou wu, he shou wu, fo-ti, fo-ti-teng, Chinese knotweed, climbing knotweed, flowery knotweed, fleece flower, and the like. He Shouwu, a Chinese man who is reputed to have lived until the age of 132, is the first consumer of this herb to be reported. Polygonum multiflorum root tuber is traditionally used in Chinese medicines as a tonic and an anti-aging remedy, particularly for hair loss and premature greying of hair. Polygonum multiflorum is bitter, sweet, and astringent and has a slight warming effect when ingested. It was used as a principal drug or main component of restorative drugs. The major origins of Polygonum multiflorum are He-nan, Guei-zhou, Sih-chuan, Hu-nan, Shan-dong, etc. According to Chinese literature, the earliest record of the utilization of Polygonum multiflorum can be traced to the Han dynasty (206 B.C.-220 A.D.).
It has been proven that the extracts of Polygonum multiflorum have the effects of prolonging the life cycle of diploid cells, prolonging the life of fruit flies and aging pelicans, reducing the level and activity of superoxidase dismutase (SOD), and increasing the DNA repair activity in aging organisms (Peng, Y., et al., World Science and Technology/Modernization of Traditional Chinese Medicine and Materia Medica (2005) 7(5):63-67 and 86).
US 2002/146467 A1 and U.S. Pat. No. 7,083,811 B2 disclose herbal compositions for the prevention and treatment of dementia comprising Polygoni multiflori Radix (Polygonum multiflorum Thunberg) and other medicinal herbs. CN 1582975 discloses a Chinese medicine for treating cerebrovascular disease and senile dementia which is prepared from five Chinese medicinal materials including fleece flower root, lotus leaf, earthworms, etc., through decocting and extracting in alcohol and then drying. CN 1621078 relates to a Chinese herbal composition, which is prepared from red sage, freeze-dried fresh pilose antler, ginsenoside, fleece flower root, sealwort, haw and rhubarb, for treating hypophrenia and dementia. CN 1742968 relates to a medicine for curing vascular dementia, which is prepared from the Chinese medicinal materials of flowery knotweed root, astragalus root, salvia root, ligusticum root, acorus root, alphinia fruit, ginkgo leaf total flavone, earthworms, leeches and gastrodia root.
One of the major components of Polygonum multiflorum is 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) as shown in FIG. 1A. TSG can be extracted and isolated using the microwave-assisted extraction process (see Wang, J. et al., (2003) Zhongcaoyao 34(4): 314-317), countercurrent technology (see Zhang, T. et al., Journal of Liquid Chromatography & Related Technologies (2003) 26(9 & 10): 1565-1577) and the method using liquid-phase extraction and chromatography (see Yan, X., Shanghai Diyi Yixueyuan Xuebao (1981) 8(2): 123-6, and CN 1215728). CN 1159015C discloses the utilization of reverse-phase chromatography to isolate the stilbene glucoside compound extracted from Polygonum multiflorum by chloroform and then by ethanol. It was proven in animal experiments that the stilbene glucoside compound is capable of preventing the damage of brain cells caused by β-amyloid protein and hydrogen peroxide, and increasing the memory capacity in mice having scopolamine dementia and Aβ dementia. Zhang, L. et al., (Clin. Pharm. J, 2005, 40(10): 749-752) discovered that 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) in Polygonum multiflorum has the effect of treating cholinergic damage in rats, and that, at a dose as low as 30 mg/kg, TSG can increase choline-acetyl-transfertase (ChAT) activity and improve M-cholinergic receptor binding capacity. CN 1159015C also teaches that 3,4′,5-trihydroxy-2-stilbenyl beta-D-glucoside can be used as an agent for treating Alzheimer's disease, vascular dementia and impairment of cognitive function.
Green tea is also reported to be capable of preventing the incidence of stroke (see Kakuda, T., Foods & Food Ingredients Journal of Japan (2001) 191: 51-55). It is found that catechin in green tea has a radical scavenging effect and can indirectly prevent dementia. JP 2005-082495 discloses that catechin and aminobutyric acid (GABA) contained in green tea have efficacy in the improvement of memory and the treatment of dementia and mental disorders.
Generally, the complexity of herbal medicines exists in not only the diversity of ingredients, but also the putative interactions between herbs. Therefore, the actions of traditional herbal medicine are totally different from those of modern western medicine, with its single-target and single-drug relationship. In view of the difficulty in identifying all the components in a simple Chinese herb, it is difficult to determine whether a synergistic and/or complementary effect is achieved by the active ingredients contained therein by scientific methods. In order to study the efficacy of a Chinese herb and to produce a therapeutic agent from a Chinese herb, it is necessary to develop an effective method to isolate, identify and purify the active ingredients in the herb.
Traditionally, the crude material of Polygonum multiflorum must be processed before use so as to remove the components emodin and physcion, which may cause the side effect of diarrhea, from the material. In the traditional processing method, dried Polygonum multiflorum is soaked and heated by steam in black soybean juice, and then is dried to obtain a product called “Radix Polygoni Multiflori.” However, during the processing, the therapeutically active ingredient will be degraded. Thus, there is still a need to develop an efficient method to process Polygonum multiflorum. Furthermore, in order to improve the efficacy of Polygonum multiflorum extract, it is necessary to develop an economical and efficient method to obtain a product that comprises maximum amounts of TSG and catechin, and a minimum amount of emodin.